Project 1. Glabe. Diversity of Amyloid Oligomer Assembly States and Roles in AD Pathogenesis The goal of this research project is to explore the mechanisms of amyloid deposition and the role of distinct assembly states of amyloid oligomers in pathogenesis in AD and in transgenic mouse models of AD. Several different types of amyloid deposits accumulate in disease brain and current evidence suggests that different types of amyloid assembly states may play distinct roles in pathogenesis. We have produced three different conformation-dependent antibodies that specifically recognize prefibrillar oligomers, fibrils and pore-like annular protofibrils that are formed from many different types of amyloids. We hypothesize that these three conformationally distinct assembly states of AC are differentially associated with AD pathogenesis. We will test the hypothesis that soluble, oligomeric or annular forms of AB are primarily associated with neuronal dysfunction and AD and DS pathogenesis. We will determine the distribution, localization and concentration of prefibrillar, annular and fibrillar amyloid deposits in several different regions of human AD brain, mild cognitively impaired and age-matched control brains. We will determine the localization and concentration of soluble oligomers, annular protofibrils and mature fibrils in transgenic animals as a function of age and examine the effect of vaccination against oligomeric and fibrillar forms of AC on the accumulation of different types of amyloid. We will biochemically characterize the various types of soluble oligomers from AD brain to determine their relationship to the various conformations of AC formed in vitro and we will compare their toxicity and interaction with neurons in vitro. The hypothesis is that the oligomers in human AD brain are related to one or more of the different conformations in vitro oligomers, but may also contain other components that either enhance or inhibit their toxicity in vitro. We anticipate that these results will help clarify which assembly states of amyloid are primarily associated with AD pathogenesis and resolve some apparent inconsistencies and conflicting data, such as the observations that the total AC amyloid deposited correlates poorly with disease and some people have large amounts of amyloid and are cognitive normal, while other brain samples that have little observable amyloid deposits are associated with cognitive dysfunction. The availability of pure and homogeneous populations of different assembly states of AC and novel antibodies that specifically recognize these different assembly states affords us a unique opportunity to examine and clarify the role of AC assembly states in Alzheimer disease pathogenesis.